Reduced DJ-1-F1Fo ATP synthase association correlates with midbrain dopaminergic neuron vulnerability in idiopathic Parkinson’s disease

Disruption in neuronal and synaptic metabolic homeostasis is a key driver of neurodegeneration in Parkinson's disease (PD). Mitochondrial activity, biomass, and efficiency are critical to this balance. While activity and biomass are well characterized in PD pathology, mitochondrial metabolic efficiency remains insufficiently explored. Our previous studies showed that the protein product of PD-associated gene DJ-1 modulates metabolic efficiency through its interaction with the F1Fo-ATP-synthase β subunit (β-sub). Here, using proximity ligation assay (PLA), we compared mitochondrial DJ-1-β-sub association in distinct mesencephalic dopaminergic (mesDA) neuronal subpopulations and their intracellular compartments of PD and control postmortem brains. In PD brains, DJ-1-β-sub-PLA was lower than control in substantia nigra pars compacta (SNpc) somata and neurites but unchanged in ventral tegmental area (VTA) neurons. In PD and control cases, the PLA signal was reduced in distal neurites of SNpc compared to VTA neurons. These intracellular and region-specific differences suggest that impaired mitochondrial efficiency may contribute to the differential vulnerability of mesDA neurons in PD.